ABSTRACT Each year upwards of 14,000 patients are diagnosed with Glioblastoma (GBM), the most malignant form of primary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options for GBM, but patients generally succumb to the disease. MicroRNAs (miR) are emerging as key regulators of cellular differentiation and proliferation; have been implicated in the etiology of a variety of cancers, including GBM. Our exciting preliminary studies show great promise for exosomes shed from induced pluripotent stem cell derived - neural stem cells (iNSC) expressing miR-124 to target brain tumors. In the mentored (K99) phase of this study, I will evaluate the immune effects mediated by miR-124 delivered locally into the tumor bed via encapsulated neural stem cells following tumor debulking. We hypothesize that miR-124 modulation by exosomes enriched in miR-124 from NSC, when delivered into the tumor resection cavity will target tumor cell proliferation and enhance T-cell mediated immune clearance of GBM cells. Once these effects are validated, in the R00 phase of the award, the potential synergy between the modulation of miR-7 and miR-124, which target AKT and STAT3 respectively will be studied to develop a sECM encapsulated iNSC delivered miR-7/ miR-124 therapeutic approach to target resected GBM. In order to ensure safety of iNSC implantation, the herpes simplex virus ? thymidine kinase suicide gene system will be incorporated. The efficacy of iNSC-miR-7/miR-124/HSV-TK will be evaluated in mouse models of GBM resection. We hypothesize that dual modulation of miR-124 and miR- 7 will target the AKT-STAT3 signaling that is critical to tumor cell growth and together with the activation of host immune system medicated tumor clearance will present therapeutic benefit. Upon validation, this microRNA based therapeutic strategies will pave path to much needed novel treatments to target GBM.